Factors to
be considered in the design of controlled release dosage form
Session Objectives
By the end of this session, students will be able to:
• Enumerate the various factors to be
considered in the design of CRDF
• Explain the biological factors affecting drug
candidate selection for CRDF
• Discuss the physico-chemical attributes of a
drug candidate in the design of CRDF
Physicochemical properties of a drug influencing design and
performance of cdds
1) Aqueous solubility
2) Partition
coefficient and Molecular size
3) Drug stability
4) Protien binding
5) Polymer
solubility (CP)
6) Polymer
Diffusivity (DP)
7) Solution
Diffusivity (DS)
8) Thickness of
polymer Diffusional path (hP)
9) Thickness of
hydrodynamic diffusion layer (hd)
10) Drug loading
dose (A)
11) Surface Area
Aqueous Solubility
Drug with good aqueous solubility, especially if
pH-independent, good for controlled release dosage forms.
E.g.- pentoxyphylline.
Drug with pH-dependent
aqueous solubility E.g.- Phenytoin or drug with solubility in nonaqueous solvents E.g.-
Steroids, are suitable for parentral (i.m.)
controlled release dosage forms
• Good
aqueous solubility with good dissolution rate.
• so,the
concentration in environment acts as driving force
• Noyes
Whitney equation gives the relationship between dissolution rate and aqueous
solubility.
dc/dt = Kd A Cs
Where,
dc/dt =
dissolution rate
Kd = dissolution rate constant
A = total surface area of the drug
Cs = aqueous saturation solubility
• Metronidazole
– very low aqueous solubility
• Enhancement
solubility – Micelle formation, complexation, co-solvency, without chemical
modification of drug molecules
Partition coefficient and Molecular size:
• Influence
permeability of the drug across the biological membranes and rate controlling membrane
• High
partition coefficient(Oil soluble drugs) – readily penetrate but cannot proceed
further
• Low
partition coefficient(water soluble drugs) – cannot penetrate the membrane
• Hence,
balance in K – permeation through biological and rate controlling membrane
• The
mechanism & the rate profile of drug release depends on the variation in
the partition coefficient.
Ex. Controlled release of ethynodiol diacetate from
matrix type silicone device.
The result shows that the magnitude of the the Q/t value
increases linearly with the increase in the partition coefficient.
• Drugs
that have lower partition coefficient are not suitable for oral CR drug
delivery system
• Drugs
that have higher partition co- efficient are also not suitable for oral SR drug
delivery system as they will not partition out of the lipid membrane once it
gets in the membrane.
Log Kn = log k0 – npCH2
Where
Kn
– partition coefficient for the compound with an alkyl chain length of n-CH2
groups
K0
– Y intercept at zero carbon number,
p CH2 – slope of
the log Kn versus n plot.
The attainment of negative slope -The effect of alkyl chain
length on the magnitude of the partition coefficient alkyl chain increases –
polymer solubility (CP) increases – solution solubility (CS)
decreases – reduction in partition coefficient (Kn).
Addition of hydrophilic functional groups, such as –OH
groups to a drug molecule tends to improve the solubility at the sacrifice of
the polymer solubility in a lipophilic polymer.
Molecular size
• Lower
Mol. wt. faster and more complete absorption
• More
than 95% of drugs are absorbed by passive diffusion
• Upper
limit of drug mol size for passive diffusion-600 Daltons
Drug pKa and ionization at physiological pH
pKa:
• pKa
– acid dissociation constant.
• Aqueous
solubility of weak acids and bases – pKa of compound and the pH of the solution
or medium.
• Acid
drugs – acidic environment
• Basic
drugs – basic environment
• Ionizable
drugs must be programmed in accordance with pH variation across the GIT
• Pka
of drug is important for selection of polymer
• Drugs
existing largely in ionized form are poor
candidates for oral Sustained
release drug delivery system
• The
pKa range for acidic drug whose ionization is pH sensitive is around
3.0-7.5 and pKa range for basic drug
whose ionization is pH sensitive is around 7.0-11.0 are ideal for optimum positive absorption
Drug stability
• Drug
degradation – hydrolysis and/or metabolism
• Drug
in solid state undergo slower degradation than drug in suspension or solution.
• Drugs
– unstable in the stomach can be placed in a slowly soluble form or have their
release delayed(enteric coated tab)
until they reach the small intestine
• Drug
– unstable in the intestine – different route of administration is
chosen(floating tab)
• E.g.:
CDDS of Nitroglycerin – Nitroglycerine administered as sublingual tablet rather
than oral tablet
Protein binding
• Drug-protein
binding serve as a depot for drug producing a prolonged release profile, especially if high degree of drug
binding occurs
• The
binding of the drugs to plasma proteins (eg.Albumin) results in retention
of the drug into the vascular space “the
drug – protein complex” which can serves
as reservoir in the vascular space for sustained drug release to extra
vascular tissue but only for those drugs
that exhibit a high degree of binding
• Drugs
+ mucin = increases absorption
• Charged
compounds – greater tendency to bind
E.g.: Diazepam
and novobiocin – 95% protien binding
• Extensive
binding to plasma proteins – long half-life of elimination for drugs – most
required property for a controlled release
Polymer solubility (CP):
• Drug
release – drug particle dissociates from crystal, dissolve into surrounding
polymer, diffuse through it.
• Drug
release at appropriate rate – adequate solubility.
• Hence
polymer solubility (CP) can be seen in all the release rate
equations of all types of controlled drug delivery systems.
• Rate of drug release α polymer solubility (CP)
• Relationship
between the drug release rate (Q/t) & the magnitude of polymer solubility
(CP) will be linear
Example:
Addition of –OH group to positions 11, 17 and 21 on the
progesterone skeleton reduces the solubility of Progesterone in lipophilic
polymer.
Esterification of –OH group increases the solubility.
Fillers (silicon earth) – increase the polymer solubility of
drugs.
Polymer Diffusivity (DP):
• Diffusion
of small molecules in a polymer structure –
energy activated process
• Diffusant molecule moves to a successive
series of equilibrium positions when it acquires activation energy for
diffusion Ed,
• The energy activated diffusion process is
frequently described by the following Arrhenius relationship.
DP
= Do e -(Ed/RT)
Do is a
temperature frequency factor
Ed is
the energy of activation of polymer for diffusion
Ed = Eb
+ Er
Eb = The energy of Intramoleculer bending
Er = The energy of intermolecular repulsion
Eb –
very high for short segment polymer chain – decreases as polymer chain becomes
longer.
Er –
increases as polymer chain becomes longer – degree of freedom becomes larger
During
model calculation and diffusion measurements – molecular diameter of a diffusant
– determining the magnitude of its polymer diffusivity
The polymer
diffusivity of a diffusant molecule must be inversely proportional to the cube
roots of its molecular weight
Polymer
diffusivity DP is also dependent upon the type of functional groups
and their stereochemical position in diffusant
The factors
affecting polymer diffusivity DP are –
Cross Linking
• DP
decreases – cross-linking of polymer increase.
• cross-linking
agent (ethylene glycol ,dimethyl acrylate)
Effect of
Crystallinity
• LDPE
has lower degree of crystallinity than HDPE
• The
crystallinity offers very low diffusion relative to the diffusion in the
surrounding amorphous structure.
• DP
decreases when density of the PE membrane increases.
FILLERS:
Fillers (silica) are often incorporated into a
polymer (silicone elastomers) to enhance its mechanical strength.
The presence of fillers was reported to affect polymer
diffusivity than cross linking and effect of crystallinity.
Solution Diffusivity (DS)
The diffusion of
solute molecules in a solution medium may be considered as a result of random
motion of molecules.
The solution
diffusion process can be discussed by void occupation model & the theory of
free volume.
DS= Do e -(En/RT)
Where,
DS
= solution diffusivity
D0 = pre exponential factor
En= energy of activation for
solution diffusion
If solute
molar volume ≥ molar volume of water then the diffusivity of the solute
molecules in the aqueous solution (at 250C) is inversely
proportional to the cube root of molar volume.
When solution diffusivity of various chemical groups was
compared on the basis of molecular volume, the relative rates found that,
Alkane >
Alcohols > Amides > Acids > Aminoacids > Dicarboxylic acids.
The diffusivity of solute molecules in an aqueous solution
usually decreases as its concentration increase. This reduction is frequently
related to the increase in viscosity that usually accompanies the
increase in solution concentration.
The effect of viscosity (μ) is related to solution
diffusivity (DS).
DS =
w / μ
Where,
w is
proportional constant.
Thickness of polymer Diffusional path (Hp)
• The
controlled release of a drug species from polymer membrane permeation &
polymer matrix controlled drug delivery system – Fick’s law of diffusion.
• Difference
in the drug release patterns is a result of the difference in the time
dependence of the thickness of their polymer diffusional path Hp
• Reservoir
type drug delivery devices with non-biodegradable and non-swollen polymers such
as silicon elastomer. The hP value is constant throughout the time
span.
• In
matrix type drug delivery systems fabricated from biodegradable polymers the Hp
in the polymer matrix as defined by the depletion zone grows progressively in
proportion to the square root of time.
Non-biodegradable hydrophilic polymers – hydroxy
ethylmethacrylate
Biodegradable polymers – polyhydroxy butyrate
Thickness of hydrodynamic diffusion layer (hd):
• Hydrodynamic
diffusion layer Hd – drug release profiles when a device is immersed
in stationary position in a solution, a stagnant layer is established on the
intermediate surface of the device.
• Thickness
of this stagnant layer is dependent on solution diffusivity (Ds) and
varies with the square root of times.
• Diffusivity
decreases – concentration increases.
• Diffusivity
reduction is frequently related to the increase in solution viscosity that
usually accompanies the increase in solute concentration.
Drug loading
dose (A)
• In
the preparation of drug delivery device varying loading doses of drug are
incorporated into the device as required for different lengths of treatment.
Q= [(2A – CP)
CP DPt]1/2
• Variation
in loading doses result only in a change in the duration of constant drug
release profiles.
Dosage size
• In
general a single dose of 0.5 – 1.0 g is considered for a conventional
dosage form this also holds for
sustained release dosage forms
• If
an oral product has a dose size greater that 500mg it is a poor candidate
for sustained release system, since
addition of sustaining dose and possibly the
sustaining mechanism will, in most cases generates a substantial volume product that unacceptably large
Surface Area:
·
The dependence of the rate of drug release on
the surface area of drug device is well known theoretically and experimentally.
·
As the surface area increases, the rate of drug
release increases in all types of CDDS
Summary
• The
physico-chemical factors affecting drug selection for CRDF are :
q Dosage
size
q Partition
coefficient and molecular size
q Aqueous
Solubility
q Drug
stability
q Protein
binding
q Pka
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